Mechanisms and Effects of Transcranial Direct Current Stimulation

James Giordano, Marom Bikson, Emily S Kappenman, Vincent P Clark, H Branch Coslett, Michael R Hamblin, Roy Hamilton, Ryan Jankord, Walter J Kozumbo, R Andrew McKinley, Michael A Nitsche, J Patrick Reilly, Jessica Richardson, Rachel Wurzman, Edward Calabrese, James Giordano, Marom Bikson, Emily S Kappenman, Vincent P Clark, H Branch Coslett, Michael R Hamblin, Roy Hamilton, Ryan Jankord, Walter J Kozumbo, R Andrew McKinley, Michael A Nitsche, J Patrick Reilly, Jessica Richardson, Rachel Wurzman, Edward Calabrese

Abstract

The US Air Force Office of Scientific Research convened a meeting of researchers in the fields of neuroscience, psychology, engineering, and medicine to discuss most pressing issues facing ongoing research in the field of transcranial direct current stimulation (tDCS) and related techniques. In this study, we present opinions prepared by participants of the meeting, focusing on the most promising areas of research, immediate and future goals for the field, and the potential for hormesis theory to inform tDCS research. Scientific, medical, and ethical considerations support the ongoing testing of tDCS in healthy and clinical populations, provided best protocols are used to maximize safety. Notwithstanding the need for ongoing research, promising applications include enhancing vigilance/attention in healthy volunteers, which can accelerate training and support learning. Commonly, tDCS is used as an adjunct to training/rehabilitation tasks with the goal of leftward shift in the learning/treatment effect curves. Although trials are encouraging, elucidating the basic mechanisms of tDCS will accelerate validation and adoption. To this end, biomarkers (eg, clinical neuroimaging and findings from animal models) can support hypotheses linking neurobiological mechanisms and behavioral effects. Dosage can be optimized using computational models of current flow and understanding dose-response. Both biomarkers and dosimetry should guide individualized interventions with the goal of reducing variability. Insights from other applied energy domains, including ionizing radiation, transcranial magnetic stimulation, and low-level laser (light) therapy, can be prudently leveraged.

Keywords: biphasic; dose–response; electrical stimulation; hormesis; hormetic; tDCS.

Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: CUNY has patents on brain stimulation with Bikson as an inventor. Bikson has equity in Soterix Medical Inc. Nitsche is on the advisory board of neuroelectrics—producing DC stimulators.

Figures

Figure 1.
Figure 1.
Schematics of the 3 major toxicological dose–response models, LNT, threshold, and hormesis, are illustrated above. Toxic responses to increasing doses of a hypothetical toxicant are represented as a percentage of untreated controls. Note that the threshold points for both the threshold and hormetic models are the same (at dose 5) and that only the hormesis model actually characterizes the observed reductions in toxicity (beneficial effects) occurring over a portion of the subthreshold range (ie, between doses 1 and 5). LNT indicates linearity no-threshold.
Figure 2.
Figure 2.
Mechanism of action of LLLT at a cellular level. Near-infrared (NIR) light is absorbed in mitochondria, leading to the activation of signaling pathways (cyclic adenosine monophosphate [cAMP], reactive oxygen species [ROS], NO) that in turn activate transcription factors such as nuclear factor kappa B (NF-kB) and activator protein 1 (AP1) (see text for details). LLLT indicates low-level laser (light) therapy; NIR, near-infrared; ROS reactive oxygen species.
Figure 3.
Figure 3.
Mechanism of action of tNIR in the brain. The transcription factor activation as discussed in Figure 1 leads to upregulation of neurotrophins such as BDNF leading to neuroplasticity (synaptogenesis) and newly formed neurons (neurogenesis). Neuroinflammation is reduced. BDNF indicates brain derived neurotropic factor; IL-1, interleukin 1; NGF, nerve growth factor; TNF-α, tumor necrotic factor α; tNIR, transcranial near-infrared.
Figure 4.
Figure 4.
Hormetic dose–response curve depicting the quantitative features of hormesis.

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